Free radicals

Properties, method of formation, stability, applications, types of reaction mechanisms, radical inhibitors, method of detection of free radicals

1. FREE RADICALS FROM, VIKAS R. MATHAD I M.PHARM. DEPT. OF PHARMACHEMISTRY SJMCP TO, H S BASAVARAJ SIR DEPT. OF PHARMACHEMISTRY SJMCP

2. CONTENTS DEFNITION PROPERTIES STRUCTURE OF FREE RADICALS METHOD OF FORMATION OF FREE RADICALS STABILITY OF FREE RADICALS APPLICATIONS OF FREE RADICALS TYPES OF REACTION MECHANISMS RADICAL INHIBITORS METHOD OF DETECTION OF FREE RADICALS

3. DEFNITION Free radicals are atoms, molecules or ions with unpaired electrons in outer shell configurations. Free radicals may have positive, negative or zero charge. Unpaired electrons cause radicals to be highly reactive. Radicals are believed to be involved in degeneration diseases & cancers.

4. PROPERTIES In gaseous state free radicals are easily formed. Most of them are formed in non polar solvents. Short lived radicals are difficult to isolate, because they are highly reactive. Long lived radicals are stable, because they exist in equilibrium with normal compound. STRUCTURE OF FREE RADICALS

5. METHOD OF FORMATION OF FREE RADICALS The homolytic cleavage of covalent bonds produces radicals. Weaker covalent bonds dissociate into radicals more than stronger covalent bonds. Thermal reaction Photochemical reaction Redox reaction

6. Thermal reaction At temperatures greater than 500°C & in the absence of oxygen, mixtures of high molecular weight alkanes break down into smaller alkane & alkene fragments. It is also called thermal cracking. It is important in the refining of crude petroleum because of the demand for lower boiling gasoline fractions. Peroxides

7. b) Azo compounds

8. 2) Photo chemical reaction Compounds having absorption bands in the visible or near violet spectrum may be electronically excited to such a degree that weak covalent bonds undergo homolyses. Examples include the halogens Cl , Br₂, & I₂, alkyl hypo chlorides, nitrites, esters, & ketones. Redox reactions The action of inorganic oxidizing & reducing agents on organic compounds may involve electron transfers that produce radical ionic species.  

9. Kolbe’s Reaction The electrochemical oxidative decarboxylation of carboxylic acid salts that to radicals, which demerize . It is best applied to the synthesis of symmetrical dimers. The reaction mechanism involves a two-stage radical process, electrochemical decarboxylation gives a radical intermediate, then two such intermediates combine to form a covalent bond.

10. b) Fenton’s reagent Ferrous ion catalyses the decomposition of hydrogen peroxide & organic peroxides.

11. STABILITY OF FREE RADICALS Free radicals are highly reactive, they reacts themselves or with other compounds. Bond dissociation energy The bond dissociation energy is correlated to free radical stability. Low bond dissociation energies reflect the formation of stable free radicals & high bond dissociation energies reflect the formation of unstable free radicals. Small energy is required for homolytic cleavage for more stable radical

12. This graph is plotted with bond dissociation energy on the Y-axis v/s various radicals on X-axis. This graph represents the energy required for the bond dissociation for the formation of free radical in simple methane radical is higher compared to energy required for formation of tertiary radical. More the bond dissociation energy, lesser will be the stablility of the radical. Order of stability 3° Radical > 2 Radical > 1° Radical > Simple Radical (more (less stable) stable)  

13. 2) Hyper conjugation The more alkyl substituents a radical carbon atom possesses, the more stabilized it becomes from hyperconjugation. The stability of radicals is increased by aromatic substituents at the radical carbon atom. The central radical carbon atom of the triphenylmethyl radical, carries three phenyl groups. Therefore the radical is highly stabilized. Unstable charges on molecules are dispersed over structure or due to presence of hydrogen attached to radical carbon atom stabilizes the molecule. Order of stability 3° Radical > 2 Radical > 1° Radical > Simple Radical (more (less stable) stable)  

14. 3) Inductive effect Radical with a electron releasing group is more stable than that of the radical with electron withdrawing group. Free radicals adjacent to an electron withdrawing group are less stable, since electron density is being taken away from what is already an electron deficient species (CF₃ or CN)

15. 4) Presence of double bond

16. More the phenyl groups or double bonds more the stability of the compound. Order of stability

17. 5) Presence of hetero atoms The more electronegative element has the least stable free radical. Order of stability Methyl Radical > Amine Radical > Hydroxy Radical > Fluorine Radical (more (less stable) stable)

18. APPLICATIONS OF FREE RADICALS Markovnikov’s Rule The rule states that with the addition of a protic acid HX an asymmetric alkene, the acid hydrogen becomes attached to the carbon with more hydrogen substituents & the halide (X) group becomes attached to the carbon with more alkyl substituents. OR The rule can be stated that the hydrogen atom is added to the carbon with the greatest number of hydrogen atoms while the X component is added to the carbon with the least number of hydrogen atoms.

19. Mechanism

20. Anti-Markovnikov’s Rule Mechanism that do not involve a carbocation intermediate may react through other mechanisms that have other regioselectivities not dictated by Markovnikov’s rule, such as free radical addition. Such reactions are said to be Anti-Markovnikov’s, since the halogen adds to the less substituted carbon, the opposite of a Markovnikov’s reaction. Here the halogen attacks the carbon with more number of hydrogen atoms across the double bond where as hydrogen will attacks the carbon with less number of hydrogen atoms across the double bond.

21. Mechanism

22. DIFFERENCES BETWEEN MARKOVNIKOV’S & ANTI- MARKOVNIKOV’S REACTION Markovnikov’s reaction Halide groups attacks the carbon with less hydrogen across double bond where as hydrogen will attack the carbon with more number of hydrogens across the double bond. Formation of primary & secondary carbocation. Ionic reaction. Rearrangement of primary carbocation to secondary carbocation. Product is 2-bromopropane Anti- Markovnikov’s reaction Halogen attacks the carbon with more hydrogen across double bond where as hydrogen will attacks the carbon with less number of hydrogen across double bond. Formation of primary & secondary radicals. Free radical reaction. Rearrangement of primary radical to secondary radical. Product is n-bromopropane

23. TYPES OF REACTION MECHANISMS 1) Free radical halogenation Step 1: Initiation Separation of halogen into two radicals by the addition of UV light. Step 2: Propagation The first step is followed by propagation directly involved in the formation of the product. Isobutane will be used in chlorination reaction. First step is abstraction of the hydrogen atom from the tertiary carbon & forms the tertiary radical. The tertiary radical then reacts with another one of the chlorine molecule to form the product. Notice that another chlorine radical is regenerated, so this reaction can go on forever as long as there are reagents.

24. Step 3: Termination Side reaction that can stop the chain reaction are called termination steps. These termination steps involve the destruction of the radical intermediates, typically by two of them coming together.

25. 2) Free radical addition reaction Anti-Markovnikov’s radical addition of haloalkene can only happen to HBr and there must be presence of hydrogen peroxide. Hydrogen peroxide is essential for this process, as it start of the chain reaction in the initiation step. Step 1: Initiation Hydrogen peroxide is an unstable molecule under heat or sun light forms two free radicals of OH. This OH radical will go on and attack HBr which will take the hydrogen and create a bromine radical. Step 2: Propagation The bromine radical will go on & attack the less substituted carbon of the alkene. This is because after the bromine radical attack the alkene & it is bonded to the less substituted carbon & a carbon radical is formed & the radical will be formed at the more substituted carbon due to induction & hyperconjugation. After formation of carbon radical , It will go on & attack the hydrogen of a HBr, by which a bromine radical will be formed again.

26. 3) Free radical rearrangement reaction Radical 1,2-rearrangement The first radical 1,2-rearrangement reported by Heinrich Otto Wieland in 1911 was the conversion of bis (triphenylmethyl)peroxide (1) to the tetraphenylethane (2). The reaction proceeds through the triphenylmethoxyl radical (A), a rearrangement to diphenylphenoxymethyl (C) & it’s dimerization. In this cyclohexadienyl radical intermediate (B) is a transition state or may be a reactive intermediate.

27. 4) Hunsdiecker reaction The  Hunsdiecker reaction is the organic reaction of silver salts of carboxylic acids with halogens to give organic halides. It is an example of halogenation reaction. Mechanism The reaction mechanism of the Hunsdiecker reaction is believed to involve organic radical intermediates. The silver salt of the carboxylic acid  1 will quickly react with bromine to form the  acyl hypohalite intermediate  2. Formation of the diradical pair 3 allows for radical decarboxylation to form the diradical pair 4, which will quickly recombine to form the desired organic halide  5. The yield of halide is primary>secondary>tertiary.

28. 5) Free radical polymerization Free radical polymerization is catalysed by organic peroxides or other reagents which decompose to give free radicals. Step 1: Initiation Organic peroxides undergo homolytic fission to form free radicals. Step 2: Propagation Free radical produced in the above step adds to an alkene molecule to form a new free radical. This free radical can attack another alkene molecule and so on.

29. Step 3: Termination The above chain reaction can come to an halt in two ways. a) Chain combination Two chains can combine at their propagating sites. b) Disproportionation Two chains undergo disproportionation, with one chain being oxidized to an alkene and the other being reduced to an alkane as a result of hydrogen atom transfer. Other polymers that can be produced by free radical chain polymerization and poly(vinyl chloride) and polystyrene.

30. RADICAL INHIBITORS Radical reaction inhibitors or simply radical inhibitors are those compounds that are capable of removing chain-carrying molecules and thereby terminating the radical chain reaction. Radical reactions can be slowed or stopped by the presence of compounds called Radical Inhibitors. An inhibitor combines with the free radical to form a stable molecule. Without an inhibitor, each initiation step will cause a chain reaction so that many molecules will react. Vitamin E & Vitamin C are thought to protect living cells from free radicals. When an inhibitor reacts with the radical, it creates a stable intermediate, and any further reactions will be endothermic and slow. Hydroquinone, oxygen & phenothiazine are some examples of radical inhibitors. Oxygen molecules can exist in the form of a diradical, which reacts readily with other radicals.

31. Hydroquinone is also often used as a radical inhibitor. Hydroquinone is a compound that contains a benzene ring attached to two hydroxyl groups on opposing ends. The carbon-hydrogen bond one each hydroxyl group interacts with a radical to from an intermediate, which then rearranges its electrons to form a non-radical compound. In this reaction, the final product does not contain any chain-carrying radicals and therefore terminates the radical reaction.

32. METHOD OF DETECTION OF FREE RADICALS Lead mirror is deposited on the inside wall of a glass tubes. These mirrors are disappeared when attacked by free radicals. So by varying distance of mirrors from the source of free radical generation & velocity of carrier inert gas, free radicals can be detected. Several radical are coloured or produce colour reaction which can be detected by colorimetry. Magnetic field is used to detect the free radicals.

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